Project I -
Neurophysiology of aversive learning and social-emotional dysfunction in young people with and at risk for schizophrenia

Neurophysiology of aversive learning and social-emotional dysfunction in young people with and at risk for schizophrenia will apply parallel tasks in the same participants to determine brain activity and connectivity with fMRI and cortical circuitry with EEG. The neurobehavioral probes will approximate those used in the rodent projects and neurophysiological measures will be related to phenotypic features and to neurophysiological data obtained in Projects II and III. Genomic data of the participants will be integrated with Project V.

Project II - Early Development of Social-Emotional Behaviors and Amygdala Function in Mice

Project PI: Edward Brodkin, M.D.,
Co-Investigator: Ted Abel Ph.D

Early development of social-emotional behaviors and amygdala function in mice will examine the effects of disrupted NMDA receptor signaling in the amygdala on BLA and central amygdala activity, as well as social and emotional behavior development, from prepubescence to postpubescence. Project II will also test pharmacologic approaches that modulate GABA signaling or epigenetic marks for rescuing social behavior development.

Project III -
Electrophysiological markers of social function

Project PI: Steven Siegel, M.D., Ph.D.

Electrophysiological markers of social function will evaluate the effects of disrupted development and functioning of glutamatergic inputs to NMDA receptors on BLA neurons on the acquisition and maintenance of normal social behavior. In vivo surface and local amygdala EEG and local field potentials, combined with local multiunit recordings, will be employed during social behaviors, as well as voltage sensitive dyes imaging (VSDI) and single unit intracellular recordings in slices from NMDA NR1 mice with disruptions of NMDA receptor signaling.

NMDA receptor hypofunction in the amygdala of schizophrenia patients will employ a series of newly establish biochemical and histologic paradigms to assess the functionality of NMDA receptors and evaluate receptor activation, protein interactions and intracellular trafficking. These experiments will be conducted in amygdala tissue of the NMDA NR1 mice in Projects II and III as well as in postmortem amygdala tissue of patients with SCZ and human fetal tissue.

Integrative genomic analyses of NMDA receptor pathway in schizophrenia will investigate genomic underpinnings for NMDAR hypofunction and its possible association with the behavioral phenotypes of affective and social functioning during development. We will examine the NMDAR pathway for common and rare genetic variants that are enriched in patients with negative symptoms and may impact the function of BLA via modulation of gene transcripts. SCZ postmortem tissue from Project IV and a large sample of youths from the GO project, where a subsample is in Project I, will be examined.